The molecular dynamics of cholesterol in bilayer membranes: A deuterium NMR study

The ²H-NMR spectra of selectively deuterated cholesterol, intercalated in egg phosphatidyl-choline, were examined. The orientation of the axis of motional averaging was calculated using the observed quadrupole splittings and the atomic coordinates. With the known orientation of the rotation axis, quadrupole splittings observed for deuterium labels on cholesterol can be related to the molecular order parameter of the sterol. In addition, knowledge of the axis orientation allows prediction of the magnitudes of quadrupole splittings for deuterium at other positions, which is useful in the choice of labelling for particular applications. Finally, preliminary relaxation time measurements yield information on the rates of anisotropic motion of cholesterol in bilayer membranes.     

Lipid bilayer polypeptide interactions studied by molecular dynamics simulation

A model membrane with a polypeptide alpha-helix inserted has been simulated by molecular dynamics at a temperature well above the gel/liquid crystalline phase transition temperature. Order parameters of the lipids and other equilibrium and dynamic quantities have been calculated. Three systems, polyglycine constrained into an alphahelical configuration, glycophorin with similarly conformationally constrained backbone and finally glycophorin free to change its backbone conformation, have been studied. In all cases there was an ordering of the chains close to the helix. This effect was, however, much smaller for glycophorin with its rather bulky side chains than for polyglycine. The dynamics of the lipids were affected by the neighbouring helix, not drastically however. Lateral diffusion and reorientational time correlations of lipids close to the helix were slower than for the bulk ones, but not more than two or three times. Thus, we did not find any evidence of bound or frozen boundary lipids.     

Detailed molecular dynamics simulations of model biological membranes containing cholesterol

Detailed molecular dynamics simulations performed to study the nature of lipid raft domains that appear in model membranes are reviewed in this paper. The described simulations were performed on hydrated bilayers containing binary mixtures of cholesterol with phospholipids and also on ternary mixtures containing cholesterol, a phospholipid with a high main transition temperature T_m, and a phospholipid with a low transition temperature T_m. These simulations provide qualitative and semi-quantitative information about cholesterol-lipid interactions and also a testing ground for major assumptions made to explain the nature of lipid rafts in model membranes.     

Understanding interaction and dynamics of water molecules in the epoxy via molecular dynamics simulation

The robust structural integrity of the epoxy plays an important role in ensuring the long-term service life of its applications, which is affected by the absorbed moisture. In order to understand the mechanism of the moisture effect, the knowledge of the interaction and dynamics of the water molecules inside the epoxy is of great interest. Molecular dynamics simulation is used in this work to investigate the structure and bonding behaviour of the water molecules in the highly cross-linked epoxy network. When the moisture concentration is low, the water molecules are well dispersed in the cross-linked structure and located in the vicinity of the epoxy functional groups, which predominantly form the hydrogen bond (H-bond) with the epoxy network, resulting in the low water mobility in the epoxy. At the high concentration, the water favourably forms the large cluster due to the predominant water–water H-bond interaction, and the water molecules diffuse primarily inside the cluster, which leads to the high water mobility and the accelerated H-bond dynamics. The variation of the bonding behaviour and dynamics of the water molecules reported here could be exploited to understand the material change and predict the long-term performance of the epoxy-based products during the intended service life.     

Interaction of Piscidin-1 with zwitterionic versus anionic membranes: a comparative molecular dynamics study

Plasma membrane of each micro-organism has a unique set of lipid composition as a consequence of the environmental adaptation or a response to exposure to antimicrobial peptides (AMPs) as antibiotic agents. Understanding the relationship between lipid composition and action of antimicrobial peptides or considering how different lipid bilayers respond to AMPs may help us design more effective peptide drugs in the future. In this contribution, we intend to elucidate how two currently used membrane models, namely palmitoyl-oleoyl-phosphtidylglycerol (POPG) and 1-palmitoyl-oleoyl-glycero-phosphocholine (POPC), respond to antimicrobial peptide Piscidin-1 (Pis-1).The computed density profile of the peptide as it moves from the bulk solvent toward the membrane core suggests that Pis-1 penetrates into the POPG bilayer less than the POPC membrane. Furthermore, we showed that the two model membranes used in this study have different behavior in the presence of Pis-1. Hence, we suggest that membrane composition could be an important factor in determining lytic ability of peptide drugs to kill a unique bacterial species.

An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:37     

Differential dynamics of the serotonin1A receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation

Abstract

The serotonin_1A receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin_1A receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3?μs, to analyze the effect of cholesterol on the structure and dynamics of the serotonin_1A receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin_1A receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.     

Interfacial water on crystalline silica: a comparative molecular dynamics simulation study

Understanding the properties of interfacial water at solid–liquid interfaces is important in a wide range of applications. Molecular dynamics is becoming a widespread tool for this purpose. Unfortunately, however, the results of such studies are known to strongly depend on the selection of force fields. It is, therefore, of interest to assess the extent by which the implemented force fields can affect the predicted properties of interfacial water. Two silica surfaces, with low and high surface hydroxyl density, respectively, were simulated implementing four force fields. These force fields yield different orientation and flexibility of surface hydrogen atoms, and also different interaction potentials with water molecules. The properties for interfacial water were quantified by calculating contact angles, atomic density profiles, surface density distributions, hydrogen bond density profiles and residence times for water near the solid substrates. We found that at low surface density of hydroxyl groups, the force field strongly affects the predicted contact angle, while at high density of hydroxyl groups, water wets all surfaces considered. From a molecular-level point of view, our results show that the position and intensity of peaks observed from oxygen and hydrogen atomic density profiles are quite different when different force fields are implemented, even when the simulated contact angles are similar. Particularly, the surfaces simulated by the CLAYFF force field appear to attract water more strongly than those simulated by the Bródka and Zerda force field. It was found that the surface density distributions for water strongly depend on the orientation of surface hydrogen atoms. In all cases, we found an elevated number of hydrogen bonds formed between interfacial water molecules. The hydrogen bond density profile does not depend strongly on the force field implemented to simulate the substrate, suggesting that interfacial water assumes the necessary orientation to maximise the number of water–water hydrogen bonds irrespectively of surface properties. Conversely, the residence time for water molecules near the interface strongly depends on the force field and on the flexibility of surface hydroxyl groups. Specifically, water molecules reside for longer times at contact with rigid substrates with high density of hydroxyl groups. These results should be considered when comparisons between simulated and experimental data are attempted.     

A niosomal bilayer of sorbitan monostearate in complex with flavones: a molecular dynamics simulation study

Bilayers prepared from sorbitan fatty acid esters (Span) have been frequently used for delivery of drugs including flavonoids. We applied molecular dynamics simulation to characterize the structure of a sorbitan monostearate (Span 60) bilayer in complex with three representative flavones, a subclass of flavonoids. At a low concentration, unsubstituted flavone, the most hydrophobic member, was able to flip over and cross the bilayer with a large diffusion coefficient. At a high concentration, it was accumulated at the bilayer center resulting in a phase separation. The leaflets of the bilayer were pushed in the opposite directions increasing the membrane thickness. Order parameter of the stearate chain of Span 60 was not affected significantly by unsubstituted flavone. In contrast, chrysin with hydroxylated ring A was lined up with the acyl chains of Span 60 with its hydroxyl group facing the membrane surface. Neither flipping nor transbilayer movement were allowed. Diffusion coefficient was only 15–25% of that of unsubstituted flavone and order parameter decreased with the concentration of chrysin. Luteolin, the most hydroxylated member, interacted mainly with the headgroup of Span 60 and assumed many different orientations without crossing the bilayer. Unlike chrysin and unsubstituted flavone the bilayer integrity was disrupted at 50?mol% luteolin. These behaviors and structures of flavones in a Span 60 bilayer can be accounted for by their hydrophobicity and sites of hydroxylation.     

Bovine pancreatic trypsin inhibitor crystals with different morphologies: a molecular dynamics simulation study

A molecular dynamics simulation study is reported for three polymorphic protein crystals (4PTI, 5PTI and 6PTI) of bovine pancreatic trypsin inhibitor (BPTI). The simulated lattice constants are in good agreement with experimental data, indicating the reliability of force field used. The fluctuation patterns of peptide chains in the three crystals are similar, and the protein structures are fairly well maintained during simulation. We observe that water forms a pronounced hydration layer near the protein surface. The diffusion coefficients of water in the three crystals are smaller than in bulk phase, and thus, the activation energies are higher. The porosity, fluctuation of peptide chains and solvent-accessible surface area as well as the diffusion coefficients of water and counterion in 5PTI are the largest among the three crystals. The diffusion of water and counterion is anisotropic, and the degree of anisotropy increases in the order of 4PTI < 5PTI < 6PTI. Despite a slight difference, the structural and diffusion properties in the three BPTI crystals are generally close. This simulation study reveals that crystal polymorphism does not significantly affect microscopic properties in the BPTI crystals with different morphologies.     

The partition and transport behavior of cytotoxic ionic liquids (ILs) through the DPPC bilayer: Insights from molecular dynamics simulation

A molecular dynamics (MD) simulation with atomistic details was performed to examine the partitioning and transport behavior of moderately cytotoxic ionic liquids (ILs), namely choline bis(2-ethylhexyl) phosphate (CBEH), choline bis(2,4,4-trimethylpentyl) phosphinate (CTMP) and choline O,O-diethyl dithiophosphate (CDEP) in a fully hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer in the fluid phase at 323?K. The structure of ILs was so selected to understand if the role of dipole and dispersion forces in the ILs distribution in the membrane can be possible. Several analyses including mass density, electrostatic potential, order parameter, diffusion coefficients and hydrogen bond formation, was carried out to determine the precise location of the anionic species inside the membrane. Moreover, the potential of the mean force (PMF) method was used to calculate free energy profile for transferring anionic species from the DPPC membrane into the bulk water. While less cytotoxic DEP is located within the bulk water, more cytotoxic TMP and BEH ILs were found to remain in the membrane and the energy barrier for crossing through the bilayer center of BEH was higher. Various ILs have no significant effect on P–N vector. The thickness of lipid bilayer decreased in all systems comprising ILs, while area per lipid increased.     

Effect of gold nanoparticle on stability of the DNA molecule: A study of molecular dynamics simulation

An understanding of the mechanism of DNA interactions with gold nanoparticles is useful in today medicine applications. We have performed a molecular dynamics simulation on a B-DNA duplex (CCTCAGGCCTCC) in the vicinity of a gold nanoparticle with a truncated octahedron structure composed of 201 gold atoms (diameter ～1.8 nm) to investigate gold nanoparticle (GNP) effects on the stability of DNA. During simulation, the nanoparticle is closed to DNA and phosphate groups direct the particles into the major grooves of the DNA molecule. Because of peeling and untwisting states that are occur at end of DNA, the nucleotide base lies flat on the surface of GNP. The configuration entropy is estimated using the covariance matrix of atom-positional fluctuations for different bases. The results show that when a gold nanoparticle has interaction with DNA, entropy increases. The results of conformational energy and the hydrogen bond numbers for DNA indicated that DNA becomes unstable in the vicinity of a gold nanoparticle. The radial distribution function was calculated for water hydrogen–phosphate oxygen pairs. Almost for all nucleotide, the presence of a nanoparticle around DNA caused water molecules to be released from the DNA duplex and cations were close to the DNA.     

On the interaction of hemocyanin with lipid bilayer membranes

Osmotic jump experiments were used to measure the ionic permeability induced in lipid vesicles by Megathura crenulata hemocyanin. It was found that this protein strongly increases the conductance of K⁺ and Cl^- through these membranes but not that of SO ₄ ⁼ . These effects were attributed to the formation of ionic channels in the vesicles. We have found that a simple first-order binding model can explain the dependence of the number of pore-containing vesicles both on the time after exposure to hemocyanin and on the protein concentration. Milder effects were attributed to a non-specific adhesion of the protein to the membrane surface. Consistent with the hypothesis of reversible association, vesicles which retained hemocyanin after step sucrose density gradient centrifugation at low ionic strength, lost most of the protein upon recentrifugation at high ionic strength. Consistent with the hypothesis of channel formation bot the above vesicle preparations transferred voltage-dependent hemocyanin channels into planar bilayers when they were made to fuse with them. It is concluded that hemocyanin can interact both specifically, by forming pores within the hydrophobic core of lipid membranes, and non-specifically, probably by means of electrostatic interaction with the surface of the same membrane.Abbreviations Hepes N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid - PC phosphatidylcholine - PE phosphatidylethanolamine - PS phosphatidylserine - DOC sodium deoxycholate     

Conjugated double bonds in lipid bilayers: a molecular dynamics simulation study

Conjugated linoleic acids (CLA) are found naturally in dairy products. Two isomers of CLA, that differ only in the location of cis and trans double bonds, are found to have distinct and different biological effects. The cis 9 trans 11 (C9T11) isomer is attributed to have the anti-carcinogenic effects, while the trans 10 cis 12 (T10C12) isomer is believed to be responsible for the anti-obesity effects. Since dietary CLA are incorporated into membrane phospholipids, we have used Molecular Dynamics (MD) simulations to investigate the comparative effects of the two isomers on lipid bilayer structure. Specifically, simulations of phosphatidylcholine lipid bilayers in which the sn-2 chains contained one of the two isomers of CLA were performed. Force field parameters for the torsional potential of double bonds were obtained from ab initio calculations. From the MD trajectories we calculated and compared structural properties of the two lipid bilayers, including areas per molecule, density profiles, thickness of bilayers, tilt angle of tail chains, order parameters profiles, radial distribution function (RDF) and lateral pressure profiles. The main differences found between bilayers of the two CLA isomers, are (1) the order parameter profile for C9T11 has a dip in the middle of sn-2 chain while the profile for T10C12 has a deeper dip close to terminal of sn-2 chain, and (2) the lateral pressure profiles show differences between the two isomers. Our simulation results reveal localized physical structural differences between bilayers of the two CLA isomers that may contribute to different biological effects through differential interactions with membrane proteins or cholesterol.     

Mechanical properties of armchair silicene nanoribbons with edge cracks: a molecular dynamics study

Silicene has been proven to be a promising material with attractive electronic properties. During the synthesis of silicene, structural defects such as edge crack are likely to be generated and such defects in silicene have impacts on its properties. Herein, molecular dynamics simulations were performed to investigate the mechanical properties of the armchair silicene nanoribbons (ASiNRs) with edge cracks. Our results showed that the mechanical properties of the ASiNRs decrease because of the existence of edge crack. Both the pristine ASiNRs and the ASiNRs with edge cracks show brittle fracture behaviours. The crack length plays an important role in determining the critical strain and fracture strength of the ASiNRs. Moreover, we investigated the effects of strain rate and temperature on the mechanical properties of the ASiNRs with edge cracks. We observed that the increasing strain rate increases the critical strain and fracture strength while decreasing the Young’s modulus. Low-strain rates also changes the expanded directions of cracks in the ASiNRs. We also found that the increasing temperature could significantly decrease the mechanical properties of the ASiNRs with edge cracks.     

New insights into the molecular mechanism of methanol-induced inactivation of Thermomyces lanuginosus lipase: a molecular dynamics simulation study

Methanol intolerance of lipase is a major limitation in lipase-catalysed methanolysis reactions. In this study, to understand the molecular mechanism of methanol-induced inactivation of lipases, we performed molecular dynamics (MD) simulations of Thermomyces lanuginosus lipase (TLL) in water and methanol and compared the observed structural and dynamic properties. The solvent accessibility analysis showed that in methanol, polar residues tended to be buried away from the solvent while non-polar residues tended to be more solvent-exposed in comparison to those in water. Moreover, we observed that in methanol, the van der Waals packing of the core residues in two hydrophobic regions of TLL became weak. Additionally, the catalytically relevant hydrogen bond between Asp²⁰¹ OD2 and His²⁵⁸ ND1 in the active site was broken when enzyme was solvated in methanol. This may affect the stability of the tetrahedral intermediates in the catalytic cycle of TLL. Furthermore, compared to in water, some enzyme surface residues displayed enhanced movement in methanol with higher Cα root-mean-square atomic positional fluctuation values. One of such methanol-affecting surface residues (Ile²⁴¹) was chosen for mutation, and MD simulation of the I241E mutant in methanol was conducted. The structural analysis of the mutant showed that replacing a non-polar surface residue with an acidic one at position 241 contributed to the stabilisation of enzyme structure in methanol. Ultimately, these results, while providing molecular-level insights into the destabilising effect of methanol on TLL, highlight the importance of surface residue redesign to improve the stability of lipases in methanol environments.     

Complex disruption effect of natural polyphenols on Bcl-2-Bax: molecular dynamics simulation and essential dynamics study

Apoptosis (programmed cell death) is a process by which cells died after completing physiological function or after a severe genetic damage. Apoptosis is mainly regulated by the Bcl-2 family of proteins. Anti apoptotic protein Bcl-2 prevents the Bax activation/oligomerization to form heterodimer which is responsible for release of the cytochrome c from mitochondria to the cytosol in response to death signal. Quercetin and taxifolin (natural polyphenols) efficiently bound to hydrophobic groove of Bcl-2 and altered the structure by inducing conformational changes. Taxifolin was found more efficient when compared to quercetin in terms of interaction energy and collapse of hydrophobic groove. Taxifolin and quercetin were found to dissociate the Bcl-2-Bax complex during 12?ns MD simulation. The effect of taxifolin and quercetin was, further validated by the MD simulation of ligand-unbound Bcl-2-Bax which showed stability during the simulation. Obatoclax (an inhibitor of Bcl-2) had no significant dissociation effect on Bcl-2-Bax during simulation which favored the previous experimental results and disruption effect of taxifolin and quercetin.     

Interaction between dihydropyridines and phospholipid bilayers: a molecular dynamics simulation

Interaction of the calcium-channel antagonist dihydropyridines (DHPs), lacidipine and nifedipine, with a phospholipid bilayer was studied using 600 ps molecular dynamic simulations. We have constructed a double layer membrane model composed of 42 dimirystoyl-phosphatidylcholine molecules. The DHP molecules locate at about 7 Å from the centre of the membrane, inducing an asymmetry in the bilayer. While lacidipine did not induce significant local perturbations as judged by the gauche-trans isomerisation rate, nifedipine significantly decreased this rate, probably by producing a local rigidity of the membrane in the vicinity of the DHP.     

Diffusion and interaction mechanism of rejuvenating agent with virgin and recycled asphalt binder: a molecular dynamics study

The quality of asphalt binder recycling is largely dependent on molecular diffusion between virgin asphalt binder, aged asphalt binder, and rejuvenator. In this study, molecular dynamics (MD) simulations were used to study diffusion and interaction mechanism of rejuvenating agent in recycled asphalt binder. The diffusion process of rejuvenator into virgin and aged asphalt binder was studied using a three-layered model. A mixture model of virgin and aged asphalt binder was built to evaluate the effect of rejuvenator on the molecular structure of asphalt binder, such as nanoaggregate behaviour and translational mobility. The simulation results of the layered model suggest that rejuvenator may improve blending efficiency of virgin and aged asphalt binder depending on temperature. The calculated inter-diffusion coefficients indicate that the rejuvenator diffuses faster into virgin asphalt binder than aged asphalt binder. The radial distribution functions of asphaltene, resin, and aromatic pairs show that rejuvenator causes the molecular structures of virgin and aged asphalt binder more similar to that of virgin asphalt binder. The rejuvenator reduces the self-association trends of asphaltene molecules, but saturates from local aggregation inside the rejuvenated asphalt binder. On the other hand, rejuvenator increases translational mobility of saturate, aromatic, resin and asphaltene fractions.     

The mechanism for the complexation and dissociation between siRNA and PMAL: a molecular dynamics simulation study based on a coarse-grained model

Abstract

The capacity of silencing genes makes small interfering RNA (siRNA) becomes potential candidates for curing many fatal diseases. Due to the low stability and delivery efficiency of siRNA, the design of amphiphilic carrier for siRNA delivery is vital for the practical gene therapy. In the present work, we explored how the complexation and dissociation of siRNA with poly (maleic anhydride-alt-1-decene) substituted with 3-(dimethylamino) propylamine (PMAL), which is a recent synthesised amphiphilic polymer and can be used in delivery of siRNAs and proteins, using traditional molecular dynamics simulations, together with steered molecular dynamics simulations. It was shown that the complexation of siRNA with PMALs can spontaneously occur, no matter what unit number of PMAL is. PMALs of different unit numbers form micelle-like structures and interact with siRNA surface. With the increase of unit number, PMAL becomes more flexible and interacts with siRNA from attachment to entanglement. The dissociation of PMAL from siRNA is an energy-consuming process. The free energy difference increases with the unit number of PMAL. The free energy for dissociation involves both the stretch of PMAL and the separation of PMAL from siRNA. Therefore, an optimal unit number of PMAL is critical for the delivery efficiency of siRNA when PMAL is used as carrier. In present work, when the radius of gyration of PMAL approaches to that of siRNA, PMAL gives a favoured both complexation and dissociation between siRNA and PMAL. Finally, we propose the mechanism of complexation and dissociation of PMAL with siRNA. The above simulation established a molecular insight of the interaction between siRNA and PMAL and was helpful for the design and applications of new PMAL-based polymers as siRNA delivery carriers.     

Conformational dynamics of the mitochondrial ADP/ATP carrier: a simulation study

The mitochondrial ADP/ATP carrier is a six helix bundle membrane transport protein, which couples the exit of ATP from the mitochondrial matrix to the entry of ADP. Extended (4×20 ns) molecular dynamics simulations of the carrier, in the presence and absence of bound inhibitor (carboxyatractyloside), have been used to explore the conformational dynamics of the protein in a lipid bilayer environment, in the presence and absence of the carboxyatractyloside inhibitor. The dynamic flexibility (measured as conformational drift and fluctuations) of the protein is reduced in the presence of bound inhibitor. Proline residues in transmembrane helices H1, H3 and H5 appear to form dynamic hinges. Fluctuations in inter-helix salt bridges are also observed over the time course of the simulations. Inhibitor-protein and lipid-protein interactions have been characterised in some detail. Overall, the simulations support a transport mechanism in which flexibility about the proline hinges enables a transition between a ‘closed’ and an ‘open’ pore-like state of the carrier protein.